Hyperphenylalaninemia results from a variety of defects involving the multicomponent phenylalanine hydroxylase system. Basic studies have already been reported which clarify these disorders by a variety of clinically applicable approaches. Using such applicable techniques which include an in vivo assessment of phenylalanine hydroxylase activity using either the deuterated or tritiated ring phenylalanine test, the cofactor release assay and measuring fibroblast reductase activity in affected patients, a clinic population of "PLU's will be examined to determine the effectiveness of these tests and the frequency of the occurrence of various defects. Liver biopsies will be obtained where permitted for corroboration. The effectiveness of treatment of cofactor and reductase defects with DOPA plus or minus 5-hydroxytryprophan will be determined. Extension of studies to parents and siblings is also contemplated to determine the probable mode of transmission of these unique disorders.